Heart is an important organ to deliver blood to the whole body. The cardiac muscle plays a key role in order for a heart to work as a pump. The cardiac muscle, though involuntary, is striated like skeletal muscle. Striated muscle is the muscle tissue named so because of its striated appearance of the sarcomere due to the alignment of dark bands (myosin filament region) and light bands (Z-line region at each end of sarcomere) caused by the arrangement of actin filaments and myosin filaments in the myofibrils. Muscle cell is an elongate fibrous cell, containing numerous myofibrils and mitochondria in its cytoplasm (sarcoplasm), and is enclosed within the cell membrane called sarcolemma (sarcoplasmic membrane).
A myofibril in the sarcoplasm consists of sarcomeres which are the assemblies of actin filaments and myosin filaments. And the thinner transverse line of Z-line exists in between sarcomeres. T-tubule is located close to the Z-line, which instantly propagates the electrical excitation transmitted over the surface of sarcolemma into a myofibril, the interior of muscle cell. The electrical excitation propagated into muscle cell is then led to sarcomere via T-tubule, thereby initiated a contraction.
Cardiac muscle made up with the reticulum of muscle fibers (cardiac muscle cells) that spirally surrounds the heart, delivers blood to the whole body by repeated autonomous contractions. When heart is overloaded for a long period, cardiac muscle tissue enlarges itself not by cell division but increasing length and width of each cardiac muscle cell. That is called myocardial hypertrophy. When weight of the heart exceeds 500 g, insufficient supply of blood to cardiac muscle cells occurs because the coronary artery or the like which supply oxygen and nutrition to cardiac muscle cells are undevelopable in compensation for the hypertrophy thereof.
Cardiomyopathy is a disease resulting from abnormality of myocardium. Heart being a life-sustaining organ, and yet non-regenerative, cardiomyopathy is a severe progressive degenerative disease thereof. Cardiomyopathy is classified into a primary cardiomyopathy such as dilated (congestive) and hypertrophic cardiomyopathy; and a secondary cardiomyopathy such as infectious cardiomyopathy. The primary cardiomyopathy is categorized into hypertrophic cardiomyopathy caused by hypertrophy of cardiac muscle and dilated cardiomyopathy caused by other factors.
Cardiomyopathic hamster, a representative animal model for hereditary cardiomyopathy, was found in 1962 and has been studied in various fields such as pathology, pharmacology and physiology. A serious cardiomyopathic subline (TO-2; hereinafter, abbreviated to “T”) not manifesting the macroscopic cardiac hypertrophy has been established from a prototype of the hypertrophic cardiomyopathic hamster BIO 14.6 (hereinafter, abbreviated to “B”).
FIG. 1 is a photograph as a drawing showing the characteristics of those cardiomyopathic hamsters. G in the left hand side of FIG. 1 is a normal Golden hamster, B in the middle is a hypertrophic cardiomyopathic BIO 14.6 hamster and T in the right hand side is a dilated cardiomyopathic TO-2 hamster. FIG. 1 (A) in the top row shows the optical microscopic feature of left ventricle for each hamster stained with hematoxylin and eosin. Necrosis, fibrosis and calcification have been observed in both B and T. The bar in (A) represents 200 μm. FIG. 1 (B) shows the horizontal cross sectional feature of left ventricle of each hamster. Compensated hypertrophy in residual myocardium is significant in B, while ventricle wall is remarkably thin in T. The bar in (B) represents 2 mm. FIG. 1 (C) in the bottom row shows precordial lead V1 of electrocardiogram for each hamster. Potentials of QRS complexes in Golden (G), BIO 14.6 (B) and TO-2 (T) are 0.55±0.06, 0.98±0.06 and 0.22±0.06 V, respectively. In (C), the vertical bar represents 0.5 V; the horizontal bar represents one second.
The present inventors have clarified that genetic abnormality common in the cardiomyopathic hamster is due to the deletion of δ-sarcoglycan gene which is one of dystrophin-associated proteins (Sakamoto, A., et al., Proc. Natl. Acad. Sci. U.S.A., 1997, 94 (13873-13878); Sakamoto, A., et al., FEBS Lett., 1999, 447, 124-128).
However, it is not appropriate to discuss the cause of the cardiomyopathy of hamsters only in view of δ-sarcoglycan deficiency since the macroscopic hypertrophy of cardiac muscle has not been observed in hamster T. Further investigation with reference to the cause of cardiomyopathy in hamster (T) has been required.